Abstract. The global tuberculosis (TB) epidemic is being perpetuated by the HIV epidemic, the increasing prevalence of diabetes in China and India, and the spread of drug-resistant Mycobacterium tuberculosis (Mtb). As a community, we are making major advances in understanding how the host responds to Mtb, and these insights have been crucial for the development of improved diagnostics, new antibiotics, host directed therapy (HDT), and vaccines. However, there are still major deficits in our understanding of the pathogenesis of tuberculosis. These knowledge gaps must be filled in if we are to continue to make progress against TB, which is now the leading cause of death from a pathogen in the world. A fundamental issue is the role of alveolar macrophages (AM). AM are tissue resident phagocytes that patrol the alveolar lung compartment and are crucial for host defense and lung homeostasis. While AM are generally accepted to the be the first cell encountered and infected by Mtb following infection of people or experimental animals, the role of AM in host defense remains murky. AM are described as the first line of defense against Mtb, and although this role is consistent with the general function of macrophages, a critical examination of the published literature reveals that this idea is unsubstantiated. For example, AM-depletion renders mice more resistant to TB, raising the possibility that AM are a protected niche for Mtb growth. Conversely, GM-CSF ko mice, which lack AM, are susceptible and succumb early after Mtb infection. Whether susceptibility arises because of the development role of GM-CSF (i.e., in AM development), or because of the effector role of GM-CSF, which can stimulate anti- Mtb activity in mature macrophages, is unknown. With the development of new insights into AM biology and new models and experimental approaches, it is now possible to transition away from the use of bone-marrow derived or peritoneal macrophages, and tackle central questions about lung macrophages in vivo. Our proposal has two aims. First, we will determine whether alveolar macrophages are required for resistance to tuberculosis, and distinguish between the role of GM-CSF in AM development vs. its effector function (Aim 1). Importantly, the finding that AM are crucial for host resistance but also provide sanctuary to Mtb, are not mutually exclusive possibilities. We previously described a role for efferocytosis (the engulfment and destruction of apoptotic cells by macrophages) in control of Mtb infection. Recently, CD47 has been shown to be a ?don?t eat me? signal that prevents cell engulfment by macrophages. CD47 bindsing to SIRPa inhibits efferocytosis. Anti-CD47 blockade disinhibits efferocytosis both in vitro and in vivo. As TNF promotes the expression of CD47 by macrophages, we will test the hypothesis that persistent CD47 expression by infected AM inhibits their efferocytosis and impairs host resistance. Thus, we envision that enhancing efferocytosis will enhance resistance to Mtb, with downstream potential as a form of HDT. The overarching goal of this R21 proposal is to define how AM, the first cell infected by Mtb, modulates host resistance during Mtb infection.